title: Paracrine activation of WNT/β-catenin pathway in uterine leiomyoma stem cells promotes tumor growth.
abstract: Uterine leiomyomas are extremely common estrogen and progesterone-dependent tumors of the myometrium and cause irregular uterine bleeding, severe anemia, and recurrent pregnancy loss in 15-30% of reproductive-age women. Each leiomyoma is thought to arise from a single mutated myometrial smooth muscle stem cell. Leiomyoma side-population (LMSP) cells comprising 1% of all tumor cells and displaying tumor-initiating stem cell characteristics are essential for estrogen- and progesterone-dependent in vivo growth of tumors, although they have remarkably lower estrogen/progesterone receptor levels than mature myometrial or leiomyoma cells. However, how estrogen/progesterone regulates the growth of LMSP cells via mature neighboring cells is unknown. Here, we demonstrate a critical paracrine role of the wingless-type (WNT)/β-catenin pathway in estrogen/progesterone-dependent tumorigenesis, involving LMSP and differentiated myometrial or leiomyoma cells. Estrogen/progesterone treatment of mature myometrial cells induced expression of WNT11 and WNT16, which remained constitutively elevated in leiomyoma tissues. In LMSP cells cocultured with mature myometrial cells, estrogen-progesterone selectively induced nuclear translocation of β-catenin and induced transcriptional activity of its heterodimeric partner T-cell factor and their target gene AXIN2, leading to the proliferation of LMSP cells. This effect could be blocked by a WNT antagonist. Ectopic expression of inhibitor of β-catenin and T-cell factor 4 in LMSP cells, but not in mature leiomyoma cells, blocked the estrogen/progesterone-dependent growth of human tumors in vivo. We uncovered a paracrine role of the WNT/β-catenin pathway that enables mature myometrial or leiomyoma cells to send mitogenic signals to neighboring tissue stem cells in response to estrogen and progesterone, leading to the growth of uterine leiomyomas.
authors.affiliation: Departments of Obstetrics and Gynecology and Medicine, Feinberg School of Medicine at Northwestern University, Chicago, IL 60611.
authors.forename: Masanori
authors.initials: M
authors.lastname: Ono
authors.forename: Ping
authors.initials: P
authors.lastname: Yin
authors.forename: Antonia
authors.initials: A
authors.lastname: Navarro
authors.forename: Molly B
authors.initials: MB
authors.lastname: Moravek
authors.forename: John S
authors.initials: JS
authors.lastname: Coon
authors.forename: Stacy A
authors.initials: SA
authors.lastname: Druschitz
authors.forename: Vanida Ann
authors.initials: VA
authors.lastname: Serna
authors.forename: Wenan
authors.initials: W
authors.lastname: Qiang
authors.forename: David C
authors.initials: DC
authors.lastname: Brooks
authors.forename: Saurabh S
authors.initials: SS
authors.lastname: Malpani
authors.forename: Jiajia
authors.initials: J
authors.lastname: Ma
authors.forename: Cihangir Mutlu
authors.initials: CM
authors.lastname: Ercan
authors.forename: Navdha
authors.initials: N
authors.lastname: Mittal
authors.forename: Diana
authors.initials: D
authors.lastname: Monsivais
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Dyson
authors.forename: Alex
authors.initials: A
authors.lastname: Yemelyanov
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Maruyama
authors.forename: Debabrata
authors.initials: D
authors.lastname: Chakravarti
authors.forename: J Julie
authors.initials: JJ
authors.lastname: Kim
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kurita
authors.forename: Cara J
authors.initials: CJ
authors.lastname: Gottardi
authors.forename: Serdar E
authors.initials: SE
authors.lastname: Bulun
mesh_terms: D000328:Adult; D000818:Animals; D060466:Axin Protein / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D004967:Estrogens / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D007889:Leiomyoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D019899:Paracrine Communication; D011247:Pregnancy; D011374:Progesterone / Q000235:genetics / Q000378:metabolism*; D058118:Transcription Factor 7-Like 2 Protein / Q000235:genetics / Q000378:metabolism; D014594:Uterine Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051153:Wnt Proteins / Q000096:biosynthesis* / Q000235:genetics; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: C491761:AXIN2 protein, human; D060466:Axin Protein; D004967:Estrogens; D009363:Neoplasm Proteins; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein; C417262:WNT16 protein, human; D051153:Wnt Proteins; C540523:Wnt11 protein, human; D051176:beta Catenin; D011374:Progesterone
keywords: WNT/β-catenin signaling; paracrine signaling; tumor biology